The Calcium Channel Inhibitor Nimodipine Shapes the Uveitogenic T Cells and Protects Mice from Experimental Autoimmune Uveitis through the p38-MAPK Signaling Pathway.

Autoimmune uveitis (AU) is a sight-threatening ocular inflammatory disorder, characterized by massive retinal vascular leakage and inflamed lesions with infiltration of the uveitogenic T cells in the retina and disorders of the T cell-related immune response in the system. Stimulation of TCRs can trigger calcium release and influx via Ca channels and then transmit signals from the surface to the nucleus, which are important for energy metabolism, proliferation, activation, and differentiation. Inhibition of Ca influx by pharmacological modulation of Ca channels may suppress T cell function, representing a novel anti-inflammatory strategy in the treatment of AU. This study investigated the effects of the l-type voltage-gated calcium channel blocker nimodipine in experimental AU (EAU). Nimodipine was found to not only decrease the clinical and histopathological inflammation score of EAU (C57BL/6J mice) but also dwindle the infiltration of uveitogenic CD4 T cells into the retina. Moreover, nimodipine decreased the effector T cells and increased the regulatory T cells in the immune system. In vitro, nimodipine reduced the effector T cell differentiation of the IRBP-specific CD4 T cells of EAU mice and LPS-stimulated PBMCs of uveitis patients. Meanwhile, nimodipine suppressed the energy metabolism, proliferation, activation, and Th1 cell differentiation of T cells. Further studies on RNA sequencing and molecular mechanisms have established that nimodipine alleviates EAU by regulating T cells response through the p38-MAPK pathway signaling. Taken together, our data reveal a novel therapeutic potential of the l-type Ca channels antagonist nimodipine in AU by regulating the balance of T cell subsets.